This invention provides an improved process and novel intermediates for preparing antihistamines. In particular, the process and the intermediates of this invention are useful in the preparation of loratadine, disclosed in U.S. Pat. No. 4,282,233, and descarboethoxyloratadine (8-chloro-6,11 -dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine) ("DCL"), disclosed in U.S. Pat. No. 4,659,716.
U.S. Pat. No. 4,659,716 discloses the following process for preparing loratadine and DCL: ##STR5##
According to this process, the tricyclic ketone (1) is coupled with Grignard reagent derived from 4-chloro-N-methylpiperidine. The alcohol (2) derived from this addition reaction is dehydrated under acidic conditions to produce compound (3). Compound (3) is then subjected to a Von Braun reaction with ethyl chloroformate to produce loratadine. DCL may be prepared by decarbalkoxylating loratadine. This process suffers from a number of serious drawbacks. The halide, 4-chloro-N-methylpiperidine, required for the Grignard reaction with the ketone (1) is accessible only by a 5 step synthesis, and is unstable at temperatures above ambient temperature. The reaction of ketone (1) with N-methylpiperidin-4-yl magnesium chloride to produce the alcohol (2) is not a high yielding reaction (about 60%) due to the ocurrence of conjugate addition (i.e., to the pyridine ring) and reduction. The dehydration of alcohol (2) to produce compound (3) is a sensitive reaction, and isomerization of compound (3) can occur. The Von Braun reaction of compound (3) to produce loratadine produces noxious chloromethane as a gaseous by-product. This noxious by-product must be decomposed chemically before discharge to the atmosphere. These problems are eliminated by the present invention.